Systemic Autoimmunity

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

Abstract

Summary: The branch is focusing on identifying the role of aberrant neutrophils and neutrophil extracellular traps in the development of autoimmune responses and end-organ damage in systemic diseases including lupus (SLE), rheumatoid arthritis (RA), inflammatory myopathies and systemic vasculitides (AAV) and autoinflammatory syndromes. During this year, our group reported that NETs not only internalize DNA but, also, several RNAs that promote inflammatory pathways in endothelial cells and that oxidative damage of nucleic acids is pathogenic in SLE. In addition, we reported new findings on how proteomic, biochemical and functional differences in neutrophil subsets in lupus patients may have implications in how these cells travel through the vasculature and how this may promote organ dysfunction through microvasculopathy in SLE. We also reported new advances on how NETs damage cartilage in rheumatoid arthritis, through a process that involves distinct post-translational modifications of NET autoantigens through carbamylation. Carbamylated NETs appear to display a distinct pathogenic effect on osteoclastogenesis, with implications for bone erosions and joint damage in RA. We continue to use sophisticated imaging and functional vascular assays to quantify blood vessel abnormalities in lupus patients. We recently completed a clinical trial to assess the role of PPAR-gamma agonists in modulating vascular function and disease activity in lupus patients, at the NIH Clinical Center . In addition, we recently reported the results of a clinical trial examining how Jakinibs modulate vascular function and immune dysregulation and found that tofacitinib favorably modulated vascular dysfunction and aberrant innate immune responses in SLE, particularly patients with a specific lupus risk polymorphism. In addition, our group reported the results of the analysis of regulation of aberrant vasculopathic innate immune responses as they become modulated by type I IFN inhibition with monoclonal antibodies. The branch uses sophisticated gene expression approaches including RNA sequencing, ATAC sequencing and single cell RNA sequencing to better understand cellular heterogeneity in autoimmune diseases and the role of specific cell subsets in mediating pathogenesis. Another aspect of the branch is to understand the genetics of childhood onset SLE, especially in the context of monogenic syndromes. In recent studies, we are expanding our expertise in neutrophil biology to understand how neutrophil dysregulation is implicated in the pathogenesis of COVId-19.